Optically active derivatives of glycidol

ABSTRACT

Optically active derivatives of glycidol are disclosed. These compounds, (2S) and (2R) glycidyl tosylate and (2S) and (2R) glycidyl 4-chloro-3-nitrobenzenesulfonate can be readily crystallized to high enantiomeric purity. Their use in other synthesis reactions is also described.

The Government has rights in this invention pursuant to Grant NumberNIH-5-R01-GM28384 awarded by the Department of Health and HumanServices.

Optically active compounds have increasingly gained importance as theability to manipulate the synthesis of other optically active compoundshas improved. A compound is optically active if its atoms are notsuperimposable upon those of its mirror image. Isomers that are mirrorimages of each other are called enantiomers. Enantiomers have the samephysical properties except for this difference in geometrical shape,i.e. mirror image. This difference however, has important consequences.

In living systems only one form of the stereoisomer generally functionsproperly. The other form typically either has no biological function orresults in harm. In nature, the desired enantiomer is naturallysynthesized. Synthetic chemists, in contrast, have rarely been assuccessful in making a pure enantiomer. They generally obtain racemicmixtures containing equal amounts of both optical forms of the molecule,i.e. dextrarotary (right-handed) and levorotary (left-handed).Consequently, these racemic mixtures do not exhibit properties basedupon optical activity.

Obtaining asymmetric molecules has traditionally involved physically orchemically resolving the desired molecule from a racemic mixture of thetwo different optical forms. A second method, the chiral pool method,involves using naturally occurring asymmetric molecules as buildingblocks for the desired asymmetric molecule. A third method has beendeveloped which involves controlling the steps of the reaction so thatonly the desired enantiomer is produced (See U.S. Pat. No. 4,471,130).

While the latter method has resulted in a tremendous advance in thefield, problems still remain. The control over the reaction process isoften not complete, and both forms of the molecule can still beproduced. Even a small amount of the undesired form of the enantiomerresults in significant loss of optical purity in the resultant mixturebecause an equal amount of the desired form of the enantiomer isassociated with the undesired form. Thus, a step which produces 90% ofthe desired enantiomer only results in 80% enantiomeric excess (% e.e.).

The titanium-catalyzed asymmetric epoxidation of allylic alcohols hasbeen important in further refining the above-described controlled stepprocess. Homochiral glycidol has been useful in the synthesis ofβ-adrenergic blocking agents (β-blockers).

However, glycidol is difficult to store and isolate because it isunstable. The in situ derivation of glycidol where the unstable glycidolis derivatized after completion of the assymmetric epoxdiation reactionrather than isolated directly from the reaction mixture has manybenefits. The derivatives are easier to handle, and they are moreadvanced synthetic intermediates than the parent glycidol. However, theability to obtain high enantiomeric purity for these glycidolderivatives can vary greatly.

In substitution reactions of these derivatives poor regioselectivityresults in a substantial deterioration in the optical purity of thestarting material. Consequently, it is desirable to find derivativeswhich approach optical purity, and which exhibit high regioselectivityin substitution reactions.

We have now discovered two such compounds that are stable and can reachhigh enantiomeric purity. The two compounds are glycidyl tosylate andglycidyl 4-chloro-3-nitrobenzenesulfonate. With recrystallization it ispossible to obtain enantiomeric-purities in excess of 90%, and thus far,for the glycidyl tosylate up to about 98% e.e.

Although racemic mixtures of glycidyl tosylate have been reported(Pierre, J. et al. Bull. Soc. Chim. Fr.: 2868 (1969); Chantemps, P. etal., C.R. Acad. Sci., Paris, Ser. C, 266:622 (1968); Nakabayashi, N., etal, Bull. Chem. Soc. Jpn., 39:413 (1966); Ichikawa, K., Yuki GoseiKagaku Kyokai Shi, 22:553 (1964)), we have now found that (2S) or (2R)glycidyl tosylate can readily be produced from allylic alcohol, andcrystallized to high enantiomeric purity.

The glycidyl tosylate compound is produced by the following reactionschemes: ##STR1##

The (2S)-glycidyl tosylate preferably is purified to at least about 90%e.e., and even more preferably at least about 94% e.e, and mostpreferably about 98.0% e.e. Optical yields up to about 98.0% e.e. havebeen obtained in accord with this invention. Purification is obtained byusing crystallization techniques which are well known in the art.

(2R)-glycidyl tosylate can be similarly produced by using (+)-DIPTinstead of (-)-DIPT. (2R) compounds can be purified to the sameenantiomeric purity as (2S) compounds.

The (2S)-glycidyl 4-chloro-3-nitrobenzenesulfonate is similarly producedas shown in the following reaction scheme: ##STR2## This compound ispreferably purified to at least about 90% e.e. and even more preferablyto at least about 94% e.e. The (2R) compound can be purified to the sameenantiomeric purity as the (2S) compound and is obtained by using(+)-DIPT instead of (-)-DIPT.

The crystallized compound is stable and can easily be stored at roomtemperature until its use is desired. The stability of those compoundsmeans that they can be used commercially as "starting materials" in thesynthesis of, for example, β-blockers. For example, a convenient,one-pot procedure can be employed to convert the glycidylp-toluenesulfonate into an important intermediate to the β-blocker,propranolol, which can be converted to propranolol by the addition of^(i) PrNH₂ and H₂ O in the reaction mixture. ##STR3##

This substitution reaction takes place with high regioselectivity, about97:3 (C₁ :C₃).

Other intermediates to β-blockers, or related compounds can be readilymade according to the following reaction scheme: ##STR4## where X istosylate or 4-chloro-3-nitrobenzenesulfonate, and ArOH is an aromaticalcohol. Any aromatqic alcohol capable of displacing the sulfonatemoiety can be used in the reaction to create the desired intermediate.Preferable aromatic alcohols are those that yield desired β-blockersupon subsequent reaction with a predetermined amine. The appropriateamine to use can be readily determined by the person of ordinary skillin the art.

The invention will be further illustrated by the examples that follow:

General

Crushed 3 Å molecular sieves (Aldrich Chemical Co.) were activated byheating in a vacuum oven at 160° C. and 0.05 mm Hg for at least 8 hours.Diisopropyl tartrate and titanium (IV) isopropoxide (Aldrich) weredistilled under vacuum and were stored under an inert atmosphere. Allylalcohol and cumene hydroperoxide (tech., 80%, Aldrich) were dried priorto use over 3 Å molecular sieves, but otherwise used as received.Dichloromethane (EM Reagent) was not distilled, but was also dried over3 Å molecular sieves. 1-Naphthol (Aldrich) was sublimed prior to use.

Melting points were determined on a Thomas Hoover capillary meltingpoint apparatus and are uncorrected. IR spectra were recorded on aPerkin-Elmer 597 spectrophotometer. ¹ H NMR spectra were recorded on aBruker WM-250 (250 MHz) spectrometer with tetramethylsilane as aninternal standard.

EXAMPLE 1 Preparation of (2S)-Glycidyl Tosylate

an oven-dried 4-1 three-necked flask equipped with a mechanical stirrer,low-temperature thermometer, Claisen adapter, nitrogen inlet and rubberseptum, was charged with activated 3 Å powdered sieves (35 g) and 1.9 1dichloromethane. D-(-)Diisopropyl tartrate (14.0 g, 0.06 mol) was addedvia cannula as a solution in 15 ml CH₂ Cl₂, washing with an additional10 ml CH₂ Cl₂. Allyl alcohol (68.0 ml, 58.1 g, 1.0 mol) was then added,the mixture cooled to -5° C. under nitrogen, and Ti(OiPr)₄ (15.0 ml,14.3 g, 0.05 mol) added via syringe. After stirring for 30 minutes,precooled (ice bath) cumene hydroperoxide (80%, 350 ml, ca. 2 mol) wasadded via cannula over a period of one hour, maintaining an internaltemperature of ≦-2° C. The reaction mixture was stirred vigorously undernitrogen at -5 to 0° C. for six hours. After cooling to -20° C.trimethyl phosphite was added very slowly via cannula, not allowing thetemperature to rise above -10° C., and carefully monitoring thereduction of hydroperoxide [TLC in 40% EtOAc/hex; tetramethylphenylenediamine spray indicator (1.5 g in MeOH:H₂ O:HOAc 128:25:1 ml);ca. 141 ml (148.9 g, 1.2 moles) of P(OMe)₃ were required for completereduction. Further excess should be avoided.] The reaction is quiteexothermic and addition took one hour. Triethylamine (175 ml, 127 g,1.26 mol) was then added, followed by addition of p-toluenesulfonylchloride (220.4 g, 1.05 mol) as a solution in 250 ml dichloromethane.The flask was stoppered and transferred to a freezer at -20° C.

After 10 hours the reaction mixture was allowed to warm gradually toroom temperature, then filtered through a pad of Celite, washing withadditional dichloromethane. The resultant yellow solution was washedwith 10% tartaric acid, followed by saturated brine, dried (MgSO₄) andconcentrated to afford an oil, from which volatile components (e.g.cumene, 2-phenyl-2-propanol, P(OMe)₃, OP(OMe)₃, etc.) were removed underhigh vacuum at 65° C. on a rotary evaporator equipped with a dry icecondenser. The residue was filtered through a short pad of silica gel(ca. 1 g per g crude oil), eluting with dichloromethane. Concentrationgave a lemon yellow oil (193.5 g), which was dissolved in ca. 175 mlwarm Et₂ O and crystallized by addition of pet. ether and cooling,seeding with pure material. Seed crystals may be obtained by purifying asmall portion of the crude oil by column chromatography (silica gel).The resulting off-white solid was recrystallized twice (Et₂ O-petether), seeding each time with pure material. (2S)-Glycidyl tosylate wasobtained as large white prisms (91.7 g, 40%); mp 46°-48.5° C.; [α]_(D)²⁵ +17.5° (c=2.13, CHCl₃), 94 % ee.

Attempts to measure the e.e. directly, via ¹ H NMR in the presence ofchiral shift reagents, or by HPLC on a chiral stationary phase, provedunsuccessful. Therefore, glycidyl tosylate was converted to thecorresponding iodohydrin, following Conforth's published procedure (J.Chem. Soc. (1959), 112). The crude iodohydrin was then directlyesterified with (R)-(+)-α-methoxy-α-(trifluoromethyl) phenylacetylchloride to give the Mosher ester, and the e.e. measurement was made byHPLC of the ester on a chiral Pirkle column, eluting with 8%iso-proponalol/hexane. The e.e. was also determined by ¹ H NMR analysisof the Mosher ester in C₆ D₆.

IR (KBr) 3075, 3000, 2935, 1598, 1495, 1448, 1405, 1362, 1310, 1295,1257, 1195, 1180, 1098, 1020, 965, 915, 875, 666, 575, 558 cm⁻¹. NMR(250 MHz, CDCl₃) δ 7.81 (d, J=8 Hz, 2H), 7.36 (d, J =8 Hz, 2H), 4.26(dd, J=3.4, 11.4 Hz, 1H), 3.95 (dd, J=6.0, 11.4 Hz, 1H), 3.16-3.23 (m,1H), 2.82 (t, J=4.5 Hz, 1H), 2.60 (dd, J=2.5, 4.75 Hz, 1H), 2.46 (s,3H). Anal. Calcd for C₁₀ H₁₂ O₄ S: C, 52.62; H, 5.30. Found: C, 52.75;H, 5.29.

By using the above described procedure glycidyl tosylate havingenantiomeric purity up to 98.0% e.e. has been obtained.

EXAMPLE 2 Preparation of (2S)-Propanolol from (2S)-Glycidyl Tosylate

In a 250-ml round-bottomed flask equipped with a rubber septum, sodiumhydride (oil free, 1.15 g, 0.048 mol) was suspended in DMF (40 ml,stored over 3 Å sieves) at room temperature under a nitrogen atmosphere.1-Naphthol (6.06 g, 0.042 mol) was added via cannula as a solution inDMF (20 ml) to produce a foamy green sludge. After 15-30 minutes, asolution of (2S)-glycidyl tosylate (94% ee, from Example 1, 9.138 g,0.040 mol) in DMF (20 ml) was added via cannula. A clear green-brownsolution resulted.

After 4 hours the reaction was judged to be complete by TLC (40%EtOAc/hex). Isopropylamine (34 ml, 0.4 mol) and water (3.4 ml, 0.19 mol)were added, the septum replaced with a cold water condenser, and thereaction was heated to reflux (bath temperature was about 90° C.) Thereaction was followed by TLC (50% CH₂ Cl₂ /hex). After 4 hours the heatwas removed, the reaction mixture diluted with water (100 ml) andextracted with ether (3×100 ml). The combined organic extracts werewashed with 1N NaOH, saturated brine, dried over Na₂ SO₄ andconcentrated under reduced pressure. Overnight drying in vacuo affordeda yellow solid (9.75 g).

This solid was dissolved in ether (100 ml), treated with gaseous HCl,and the resulting white solid (10.62 g) collected by suction filtration.Recrystallization from methanol-ether afforded 7.11 g (60%) of(2S)-propranolol hydrochloride as white crystals, mp 192°-193.5° C.;[α]²¹ -25.7° (c=1.23, EtOH). Anal. Calcd for C₁₆ H₂₂ ClNO₂ : C, 64.96:H, 7.50; N, 4.74. Found: C, 64.76; H, 7.61; N, 4.66. 1.5 g of slightlyoff-white crystals were obtained as a second crop. Recrystallizationafforded an additional 1.18 g (10%) of propranolol hydrochloride, mp191.5°-194° C.; [α]_(D) ²¹ -26° (c=0.94, EtOH).

EXAMPLE 3 Preparation of (2S)-glycidyl 4-chloro-3-nitrobenzenesulfonate

(2S)-Glycidyl 4-chloro-3-nitrobenzenesulfonate was prepared using4-chloro-3-nitrobenzenesulfonyl chloride instead of p-toluenesulfonylchloride, according to the method described in Example 1. Crude crystals(mp 49°-54° C., 41% yield) which were obtained by the crystallization ofan oil from diethyl ether-pet. ether mixture, were recrystallized fromethanol-ethyl acetate mixture to give pure crystals, mp 54.7°-55.2° C.,94% e.e.

The preparation of the Mosher ester and the ee measurement of the esterwere made according to the method described in Example 1.

IR(KBr) 3105, 3015, 1605, 1573, 1541, 1400, 1385, 1363, 1339, 1252,1197, 1190, 1170, 1159, 1107, 1056, 995, 979, 963, 945, 922, 914, 899,868, 842, 779, 767, 759, 670, 647, 591, 576, 533, 494, 452, cm⁻¹.

NMR (250 MHz, CDl₃) δ 8.43 (d, J=2 Hz, 1H), 8.05 (dd, J=2.1, 8.5 Hz,1H), 7.79 (d, J=8.5, 1H) 4.51 (dd, J=2.8, 11.6 Hz, 1H) 4.04 (dd, J=6.5,11.6 Hz, 1H) 3.23 (m, 1H), 2.87 (t, J=4.5, 4.5 Hz, 1H), 2.6 (dd, J=2.5,4.4 Hz, 1H).

This invention has been described in detail including the preferredembodiments thereof. However, it will be appreciated that those skilledin the art, upon consideration of this disclosure, may makemodifications and improvements thereon without departing from the spiritand scope of the invention as set forth in the claims.

We claim:
 1. A compound of the formula ##STR5## produced from allylicalcohol and recrystallized to high enantiomeric purity.
 2. The compoundof claim 1 purified to at least about 90% e.e.
 3. The compound of claim1 purified to at least about 94% e.e.
 4. A compound of the formula:##STR6## produced from allylic alcohol and recrystallized to highenantiomeric purity.
 5. Th compound of claim 4 purified to at leastabout 90% e.e.
 6. The compound of claim 4 purified to at least 94% e.e.7. A compound of the formula ##STR7## produced from a mixture containingits enantiomer wherein the compound has been recrystallized to anoptical purity of at least about 94% e.e.
 8. A compound of the formula##STR8## produced from a mixture containing its enantiomer wherein thecompound has been recrystallized to an optical purity of at least about94% e.e.